With an environment demanding increased public disclosure of information about implantable devices, med-tech powerhouse Medtronic (Minneapolis) released its 2006 Medtronic CRM Product Performance Report (First Edition, Volume 54), incorporating up-to-date information about pacemaker, implantable cardioverter-defibrillator (ICD) and implantable lead performance. The 177-page report is available at www.CRMPPR.medtronic.com and also distributed to more than 27,000 physicians. Medtronic said that the data contained in its 2006 report are generated from analyses of returned products and postmarket studies and are applicable to the more than 6.6 million total implanted devices and more than 3.4 million currently implanted (active) devices in the U.S., the company said.
According to spokesperson Kyra Schmitt, while the company has been doing these kinds of reports for more than 20 years (dating back to 1983), some changes were made for this year’s version. These, she said, could be linked to the industry’s desire to standardize how this type of data is presented.
One new change the company made, she told Cardiovascular Device Update, was to break down product survivals into two categories: malfunction-free survival and all-cause survival. Malfunction-free survival represents “the probability for a device to survive without malfunction,” excluding normal battery depletion. All-cause survival represents the probability for a device “to survive a period of time without malfunction and without normal battery depletion. For example, if a device survival probability is 95% after 5 years of service, then the device has a 5% chance of being removed due to normal battery depletion or malfunction.”
The survival estimates are based primarily on “return product analysis,” according to the report, an approach it terms “suitable because a significant number or explanted generators are returned for analysis.” But the report all increases the number of malfunctions and normal battery depletions using the company’s estimates of underreporting. Noting that that “all product performance reports are not created equal,” Medtronic asserts that it is the only company to use both returned product analysis and also multicenter clinical studies to monitor performance.
Schmitt said another thing that distinguishes Medtronic from its competitors is that it includes lead performance data in its report instead of providing survival estimates based solely on returned product analysis. The company’s lead survival estimates include both lead hardware failure and lead-related medical complications. “If you ask certain healthcare professionals what is the kind of data that they need, I think that’s a big part of it, because that system does not work without a lead,” said Schmitt.
“For every patient, the quality of their device means everything,” said Steve Mahle, executive vice president of Medtronic and president of the company’s Cardiac Rhythm Management business, in a statement. “Over the past 20 years, Medtronic has continually improved our performance reports based on physician feedback. Our goal is to provide device performance information in a manner that is forthright, meaningful and useful for patient care.”
NMT endpoint in MIST: incomplete picture
The picture provided by NMT Medical’s (Boston) MIST (Migraine Intervention with STARflex Technology) trial – the results of which were presented during last month’s annual meeting of the American College of Cardiology (Bethesda, Maryland) at Atlanta’s World Congress Center – can best be described as, well, not very focused. The trial was designed to see whether repairing the patent foramen ovale (PFO), a hole in the wall between the two upper heart chambers that fails to close after birth, can relieve migraine headache pain. While the study showed that closing the PFO with an implant relieves migraine pain in some patients, the trial missed its primary endpoint of total elimination of headache, perhaps too lofty a goal – some at the meeting were saying – for this first prospective, randomized, double-blinded study to examine the relationship between the implant and the condition.
Co-lead investigators Peter Wilmshurst, MD, a consultant cardiologist at the Royal Shrewsbury Hospital (Shrewsbury, UK), and Andrew Dowson, director of the King’s Headache Service, Kings College Hospital (London), jointly presented the results. They reported that the 147-patient UK-based study of NMT’s Starflex implant reduced migraine burden by about 37%, compared with about 17% in patients undergoing a surgical sham – that is, a procedure with no implant. The results were significant, but fell short of the trial’s goal of a 40% improvement. Dowson said that the number of patients who reported a 50% reduction in the total number of headache days – 42% of the Stareflex patients and 23% of the sham patients – was statistically significant and compared favorably to numbers that would be expected in a trial for a migraine medication.
While NMT president and CEO John Ahern said he was disappointed that the study did not hit its primary endpoint, he expressed hope that future MIST studies would benefit from this early trial and serve as a building block toward an ultimate FDA approval.
“Although we were disappointed that MIST did not satisfy its endpoints, the study was designed to help demonstrate clinical relevancy and not to obtain a specific regulatory approval,” Ahern said in a statement. “The study has provided us with significant data that we intend to incorporate into our MIST II and MIST III studies.”
In a conference call after the MIST presentation, Ahern said the company is in the process of identifying elements of the trial that it can take to the FDA to help make any relevant changes to the MIST II trial, currently enrolling 600 patients, “so that it’s a more robust study with a higher chance of success.”
Dowson added another tantalizing fragment to the still incomplete puzzle during the conference call when he pointed to another interesting trend in the MIST data, a trend towards better outcomes for the Starflex patients, particularly after they stopped taking aspirin and clopidogrel, about a month after the procedure. “What in fact happened is that the aspirin and clopidogrel could actually have overlapped slightly into the observation phase,” he said, adding that this prophylactic medication wash-out period could have acted as a “sort of confounding factor bet-ween the two groups for a part of that first month.”
While the image may not be complete, at least one piece does appear to be consistent: The study found that out of 432 migraine-with-aura patients initially screened for the trial, more than 60% had a right to left shunt. A shunt is a heart defect, which allows blood to cross from the right to left chambers of the heart, bypassing the lungs. Of those patients, almost 40% had a moderate or large PFO, six times greater than the general population.
Prudential (New York) analyst Lawrence Biegelsen wrote in a research note that lack of discussion of safety data in the PFO arm of the trial could be a cause for concern. “Safety was given short shrift during the presentation in our view, and this may be a key obstacle to acceptance by neurologists,” he said.
Conor launches dual-drug DES strategy
Conor Medsystems (Menlo Park, California) last month launched a strategy for placing two drugs on a drug-eluting stent (DES), via an agreement with Novartis Pharma (Basel, Switzerland), thus giving it a large push to differentiate itself from other DES makers now on the U.S. market or about to enter it. The company exercised an option to obtain a worldwide, non-exclusive license from Novartis to the compound pimecrolimus (Elidel) for use with its CoStar stent. The CoStar is engineered with tiny holes, or reservoirs, into which a drug is loaded, for elution onto the artery, a system that Conor sees as more specifically engineered for drug delivery from a stent than the initial DES devices.
In March 2005, the companies unveiled an agreement to evaluate three Novartis pharmaceutical agents – imatinib mesylate, pimecrolimus and a pre-commercial compound, midostaurin – for the potential development of a product combining a Novartis compound with Conor’s reservoir-based DES. Conor said it selected pimecrolimus for this licensing deal based on preclinical studies of the three compounds in combination with its stent platform.
Frank Litvack, CEO of Conor, told CDU that the agreement enables the launch of a unique three-arm trial in the Middle East and Europe “later this year,” named GENESIS, to explore a system for delivering two drugs off of the company's CoStar stent. The control arm will use its initial drug, paclitaxel, alone on a stent; the second will use pimecrolimus alone; and the third will use both the paclitaxel and pimecrolimus.
The DES will be engineered to first release the pimecrolimus drug into the artery to prevent early inflammation, with the paclitaxel then releasing more slowly “to have second impact on later proliferation,” Litvack said. The goal will be to develop a stent that targets high-risk patients, such as diabetics, he said. In this strategy, what is left is just the bare-metal stent, he emphasized.
While bare-metal stents have been getting heavy negative press these days, Litvack said that after the first six to eight months they are not what is responsible for any restenosis and are highly safe. “In terms of long-term safety,” he said, “most people would stay with bare-metal stents.” Once in place, he said they are “extremely inert.” Conversely, he said that there is a core of concern and opinion that first-generation DES devices, which remain in the body with the polymer used for drug loading, may have problems over the longer-term, primarily in producing thrombosis. And he surmised that, currently, many patients with these devices are at risk for late-stage thrombosis and possible death.
Again assuming trial success and FDA approval, Litvack said that he is not concerned about the large market head-starts by the Cypher and Taxus DES devices, or by those poised to enter the market. He said he believes Conor is “neck-and-neck” with Med-tronic (Minneapolis) and others entering the final turn toward FDA approvals, adding that Conor’s stent design is “clearly superior” and that its trials will prove it so. “We believe we have a product that has many attributes that will make it attractive to physicians,” he said. “It’s extremely deliverable, and it’s not coated – it’s a reservoir-based technology.” Its other highly positive features include strong trial efficacy in Europe and being “the only product that eliminates the drug and the polymer,” he said.